KR100388880B1 - Composition Comprising Morphine, Polypyrrolidone and a Polyalkyleneoxide - Google Patents

Abstract

Morphine containing compositions, and morphine containing formulations are disclosed for morphine treatment. Also disclosed are methods of using these compositions and formulations for the treatment of morphine.

Description

Composition Comprising Morphine, Polypyrrolidone and a Polyalkyleneoxide

Morphine is a powerful anesthetic analgesic that is primarily used to relieve pain. Morphine is also used in the treatment of dyspnea due to heart disease, in the treatment of pulmonary edema and cold, as an antispasmodic, and in the prevention of diarrhea. The most important actions of morphine are analgesic, hypnosis, respiratory depression, central nervous system inhibition, and local anesthesia. Morphine is effectively administered by injection, but pharmaceutically acceptable means of oral administration of morphine as analgesics, anesthetic aids, antitussives, and nonspecific diarrhea inhibitors are insufficient in pharmaceutical and medicinal techniques.

Summary of the Invention

In view of the foregoing, it is obvious that there is a serious need for improved morphine delivery means for the therapeutic effect of morphine. Accordingly, it is an object of the present invention to provide novel therapeutic compositions comprising morphine and novel formulations comprising morphine, wherein the therapeutic compositions or formulations of these two inventions provide novel methods of administering morphine for the desired treatment of morphine. will be. The present invention provides new and unique means of administering morphine as compared to intramuscular, subcutaneous and intravenous administration.

The present invention relates to novel therapeutic compositions comprising morphine. The present invention also relates to novel formulations comprising morphine. The invention also relates to a method of administering a therapeutic composition comprising morphine to provide an analgesic effect. The present invention also relates to a method of administering a morphine delivery formulation to provide an analgesic effect.

The drug morphine component included in the present invention includes (5α, 6α) -7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol. Representative morphine of the present invention is a morphine base, a pharmaceutically acceptable salt of morphine, a pharmaceutically acceptable inorganic salt, a pharmaceutically acceptable organic salt, morphine hydrobromide, morphine hydrochloride, morphine mucate, morphine N-oxide, morphine sulfone Pate, Morphine Acetate, Morphine Monobasic Phosphate, Morphine Dibasic Phosphate, Morphine Inorganic Salt, Morphine Organic Salt, Morphine Acetate Trihydrate, Morphine Ratio (heptafluorobutyrate), Morphine Ratio (methyl carbamate), Morphine Ratio ( Pentafluoropropionate), morphine ratio (pyridine-3-carboxylate), morphine ratio (trifluoroacetate), morphine bitartrate, morphine chlorhydrate and morphine sulfate pentahydrate Contains ingredients.

<Example 1>

Novel therapeutic compositions comprising morphine selected from the group consisting of morphine and pharmaceutically acceptable salts of morphine were prepared as follows.

First, 432 g of morphine sulfate pentahydrate, 963 g of poly (alkylene oxide) having a molecular weight of 300,000, and 90 g of poly (vinyl pyrrolidone) having an average molecular weight of 40,000 were added to the mixing bowl and dried for 10 to 12 minutes. Mixed. Then, 404 g of denatured anhydrous alcohol was slowly added to the blended composition forming material with continuous mixing for 15 minutes. The wet granules thus prepared were then passed through 20 mesh screens, dried at room temperature at 25 ° C. for 18 hours and then through 16 mesh screens. The screened granules were transferred to a planetary mixer and 14.9 g of calcium stearate was added with constant mixing to obtain a therapeutic composition. The composition was compressed to obtain a tablet comprising 250 mg of the therapeutic composition containing 70 mg of morphine sulfate. The tablets were compressed under 10 ton pressure to give sustained release morphine sulfate tablets.

<Example 2>

Therapeutic compositions prepared by the present invention comprise 50 ng to 120 mg of a component selected from the group consisting of morphine, morphine bases, morphine salts, and morphine derivatives; From 5 mg of poly (alkylene oxide) having a molecular weight of 100,000 to 650,000 selected from the group consisting of poly (methylene oxide), poly (ethylene oxide), poly (propylene oxide), poly (isopropylene oxide) and poly (butylene oxide) 750 mg; 0.5 mg to 80 mg of poly (vinyl pyrrolidone) having an average molecular weight of 3,000 to 350,000; And 0-10 mg of a lubricant represented by a component selected from the group consisting of magnesium stearate, calcium stearate, potassium oleate, stearic acid and sodium stearate. The therapeutic composition may contain other ingredients such as colorants, compression aids and binders. The composition was pressed with a compressive force of 1/8 to 10 tons to obtain a tablet for oral administration containing morphine sulfate.

The therapeutic composition may be compressed dry to form a tablet for oral administration. For example, a pharmaceutically acceptable base of morphine, or hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, laureate, borate, benzoate, lactate, phosphate, Pharmaceutically acceptable salts of morphine, represented by tosylate, citrate, maleate, fumarate, succinate, tartrate and lead sillate; Tablet excipients represented by 0 to 750 mg of microcrystalline cellulose and 5 to 750 mg of carboxymethylcellulose, such as sodium carboxymethylcellulose having a molecular weight of 10,000 to 800,000; Binders represented by poly (vinyl pyrrolidone), hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin; And a mixture of dry powder ingredients comprising lubricants such as stearic acid, calcium stearate and magnesium stearate, sieved, sieved, mixed with any ingredients such as surfactants and flavoring agents and fed to a tablet press, and then the mixture Pressurized to give a dry compressed morphine tablet for oral administration. During any of the preparations of the present invention, the therapeutic composition prepared by the wet granulation or dry granulation technique comprises a semipermeable polymer wall comprising cellulose acylate, and an outlet means for delivering morphine at a controlled sustained delivery rate through it for several hours. Can be surrounded by.

<Example 3>

First, morphine composition was added by adding 1728 g of morphine sulfate pentahydrate, 3852 g of poly (ethylene oxide) having a molecular weight of 200,000, and 360 g of poly (vinyl pyrrolidone) having an average molecular weight of 40,000 to a planetary mixing bowl. Formulations are provided by the present invention by making. The dry material was then mixed for 10 minutes. Then, 1616 g of modified anhydrous ethyl alcohol was slowly added to the blended material while mixing continued for 15 minutes. The wet granules just prepared were then passed through a 20 mesh screen, dried at room temperature for 20.5 hours, and passed through a 16 mesh screen. The granules were then transferred to a planetary mixer, mixed and lubricated with 59.8 g of magnesium stearate.

Then, a push composition was prepared as follows. Initially, 3910 g of hydroxypropylmethylcellulose having an average molecular weight of 11,200 was dissolved in 45,339 g of water to obtain a binder solution. Next, 101 g of butylated hydroxytoluene was dissolved in 650 g of modified anhydrous alcohol. About 2.5 kg of hydroxypropylmethylcellulose / water solution was added to the butylated hydroxytoluene / alcohol solution with continued mixing. The remaining hydroxypropylmethylcellulose / water solution was then added to the butylated hydroxytoluene / alcohol solution with continued mixing to complete the binder solution formulation.

36,000 g of sodium chloride was then sized using a Quadro Comil® mil used to reduce the particle size of sodium chloride. Fluid air mil is another mill used to size materials with a 21 mesh screen. Subsequently, 1,200 g of ferric oxide were passed through a 40 mesh screen. Next, all screened materials, 76,400 g of pharmaceutically acceptable poly (ethylene oxide) with a molecular weight of 7,000,000 and 2520 g of hydroxypropylmethylcellulose with an average molecular weight of 11,200, were placed in a Glat Fuid Bed Granuator bowl. Added. The bowl was attached to the granulator and the granulation process started for granulation. The dry powder was then air suspended and mixed for 10 minutes. The binder solution was then sprayed onto the powder from three nozzles. Granulation conditions were monitored during the process as follows: total solution spray rate 800 g / min, inlet temperature 43 ° C. and preparation air flow rate 4300 m ³ / hour.

While spraying the binder solution, the filter bag was shaken for 10 seconds every 1.5 minutes to release any possible powder precipitates. At the end of the spraying of the solution, 45,033 g of the coated granulated particles continued to dry for 35 minutes. After turning off the machine, the coated granules were removed from the granulator.

The coated granules were sized using quadro comil with an 8 mesh screen. The granulate was transferred to Tote Tumbler for mixing and lubricated with 281.7 g of magnesium stearate.

The morphine sulphate pentahydrate drug composition and the push composition were then compressed with a Kilian® tablet press to obtain a bilayer tablet. Initially, 434 mg of morphine sulphate pentahydrate composition was added to the die cavity to precompress, then 260 mg of push composition was added, and the layer was pressed under a pressure head of about 3 metric tons to 1.78 cm (0.700 ") × An elliptical contact layer structure of 0.95 cm (0.375 ") was obtained.

The two layered structure was coated with a semipermeable wall. The wall forming composition consisted of 95% cellulose acetate containing 39.8% acetyl and 5% polyethylene glycol with a molecular weight of 3350. The wall forming composition was dissolved in acetone: water (95: 5 weight: weight) cosolvent to obtain a solution with a solid content of 4%. The wall forming composition was sprayed on or around the bilayer structure in a 24 "Vector Hi® coater.

Next, two 0.762 mm (30 mil) exit passages were drilled through the semipermeable wall to connect the drug layer with the exterior of the administration system. The remaining solvent was removed by drying for 48 hours at 50 ° C. and 50% relative humidity. The osmotic formulation was then dried at 50 ° C. for 4 hours to remove excess moisture. Formulations prepared with this process provide 28.8% morphine sulfate pentahydrate, 64.2% poly (ethylene oxide) with a molecular weight of 200,000, 6% poly (vinyl pyrrolidone) with a molecular weight of 40,000, and 1% of magnesium stearate. The push composition is 63.675% of poly (ethylene oxide) with a molecular weight of 7,000,000, 30% of sodium chloride, 5% of hydroxypropylmethylcellulose with a molecular weight of 11,200, 1% ferric oxide, 0.075% of butylated hydroxytoluene, and 0.25% of magnesium stearate. Was done. The semipermeable wall consisted of 95% by weight cellulose acetate containing 39.8% acetyl, and 5.0% by weight polyethylene glycol having a molecular weight of 3350. The formulation included two 0.762 mm (30 mil) passages and it had an average release rate of morphine sulfate of 5 mg / hr.

In further embodiments, the formulation is a component selected from the group consisting of cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester ethers, cellulose acylates, cellulose disylates, cellulose triacetates, cellulose acetate butyrates, and the like. 65 to 100% by weight of the cellulose polymer. In addition, the wall may comprise 0 to 40% by weight cellulose ether component selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose, and 0 to 20% by weight polyethylene glycol. The total amount of all components constituting the wall is 100% by weight. Semipermeable polymers useful for wall preparation of formulations are disclosed in US Pat. Nos. 3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,111,201. These patents were assigned to Alza Corporation (ALZA Corporation, Palo Alto, CA), the assignee of the present invention.

In another preferred preparation the wall comprises ethyl cellulose, which is a selective permeable cellulose ether. Ethyl cellulose includes an ethoxy group having a degree of substitution (DS) of about 1.4 to 3 (equivalent to an ethoxy content of 40 to 50%) and having a viscosity of 7 to 100 centipoises or more. More specifically, the wall comprises 45 to 80% by weight ethyl cellulose, 5 to 30% by weight hydroxypropylcellulose, and 5 to 30% by weight polyethylene glycol (100% by weight of all components constituting the wall are 100% by weight). %being). In another embodiment, the wall comprises 45 to 80% by weight ethylcellulose, 5 to 30% by weight hydroxypropylcellulose and 2 to 20% by weight polyvinyl pyrrolidone (total weight of all components constituting the wall Percent is 100% by weight). Ethylcellulose polymers are known from US Pat. No. 4,519,801 assigned to Alza Corporation, Palo Alto, CA.

<Example 4>

In the formulations provided by the invention, the drug composition comprises 10 to 98% by weight of morphine, morphine base, morphine salt or morphine derivative; 10 to 80% by weight of poly (alkylene oxide) having a molecular weight of 100,000 to 650,000, or 10 to 80% by weight of carboxymethylcellulose such as sodium carboxymethylcellulose or potassium carboxymethylcellulose having a molecular weight of 10,000 to 400,000; 1 to 20% by weight of poly (vinyl pyrrolidone), hydroxypropylcellulose or hydroxypropylmethylcellulose; And 0.25-10% by weight of a lubricant such as magnesium stearate. In the formulation, the push composition comprises 40 to 99% by weight of poly (alkylene oxide) such as poly (ethylene oxide) having a molecular weight of 3,000,000 to 7,750,000, or 20 to 99% by weight of alkali carboxymethylcellulose having a molecular weight of 500,000 to 1,000,000; Magnesium sulfate, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium acid phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, and raffinose, sucrose, glucose, lactose, fructose, sodium chloride fructose And 0 to 80% by weight osmotic agent known as an osmotic effective solute typified by carbohydrates such as potassium chloride dextrose; Hydroxy with a molecular weight of 7,500 to 75,000 selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyisopropyl cellulose, hydroxybutyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, hydroxypropyl butyl cellulose 0.25-25 wt% alkylcellulose; Ferric chloride from 0 to 3 weight percent; d-α tocopherol, dl-α tocopherol, d-α tocopherol acetate, dl-α-tocopherol acetate, d-α tocopherolic acid succinate, dl-α tocopherolic acid succinate, ascorbyl palmitate, butylated hydroxy 0 to 3% by weight of an antioxidant represented by anisole, butylated hydroxytoluene, and propyl gallate; And 0 to 3% by weight of a lubricant represented by magnesium stearate, calcium stearate, corn starch, potato starch, bentonite, citrus pulp and stearic acid (100% by weight of the total weight of all components constituting the push composition. being).

As used herein, “outlet means” include means and methods suitable for the metered release of the beneficial drug morphine from the formulation. The outlet means includes one or more passageways, orifices, etc., through the walls in communication with the morphine in the formulation. The expression "one or more passageways" includes apertures, orifices, bores, pores, porous elements through which drugs can move, hollow fibers, capillaries, porous sheaths, porous inserts, and the like. do. In addition, the expression includes materials that erode in the fluid environment of use, or leach from the wall to provide one or more passageways in the formulation. Representative materials suitable for forming one or more passages and multiple passages are removed by erosive poly (glycolic) acids, poly (lactic) components in the walls, gelatinous filaments, poly (vinyl alcohol), fluids to remove pores. Leaching materials such as polysaccharides, salts, oxides and the like that form. The passageway or multiple passageways can be formed by filtering substances such as sorbitol, lactose, fructose and the like from the wall. The passageway can have any shape, such as round, triangular, square, oval, etc. to assist in the metered release of morphine from the formulation. The formulation may consist of one or more passageways in a spaced apart relationship, or one or more passageways on a single surface of the formulation. Passages and equipment to form passages are disclosed in US Pat. Nos. 3,845,770, 3,916,899, 4,063,064, and 4,088,864. Governed sized passageways formed by leaching are disclosed in US Pat. Nos. 4,200,098 and 4,285,987.

Examples of solvents used for the purposes of the present invention include inorganic or organic solvents that do not adversely affect the materials and final walls in the formulation, or the final composition. The solvent broadly includes components selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene Glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, chloroform, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, Benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, and aqueous / ratios such as acetone / water, acetone / methanol, acetone / ethyl alcohol, methylene dichloride / methanol and ethylene dichloride / methanol There is an aqueous mixture.

Example 5

Another representative formulation provided by the present invention is as follows: Initially, 116.1 g of morphine sulfate pentahydrate, 81.45 g of poly (ethylene oxide) having a molecular weight of 200,000, and 81.45 g of poly (ethylene oxide) having a molecular weight of 300,000 were added. Formulated in the blender at low speed for 2 minutes. Then 78 g of poly (vinyl pyrrolidone) having a molecular weight of 40,000 and 500 mL of ethanol were combined for about 1 hour. 126 mL of the poly (vinyl pyrrolidone) / ethanol blend was then slowly added to the dry ingredients while blending in a mixer at low speed. The granulation was dried overnight and then passed through a 0.846 mm (0.0333 ") screen. Then, 2.9 g of magnesium stearate (1% of the final granulation) was blended into the granulation for 1 minute using a low speed mixer.

Next, a 0.7 "by 0.375" elliptical formulation of 17.8 x 9.5 mm was pressed in a press with 1 ton compaction force. The pressed layer consists of 517 mg of morphine granulation, 310 mg of a fluid absorbent expandable push composition comprising 197.6 mg of poly (ethylene oxide) with a molecular weight of 7,000,000, 93.0 mg of sodium chloride, 15.5 mg of hydroxypropylmethylcellulose with a molecular weight of 11,200, and 3.1 mg of ferric oxide. , 0.8 mg magnesium stearate, and 0.2 mg butylated hydroxytoluene.

The push granulate was fluid bed granulated at 120 kg scale on a glass fluid bed granulator. The binder solution was obtained by dissolving hydroxypropylmethylcellulose and butylated hydroxytoluene in water and ethanol. This solution was sprayed onto the poly (ethylene oxide), sodium chloride, hydroxypropylmethylcellulose and ferric oxide blends while fluidizing the blend to form granules. The granulate was dried and then milled using a fluid air mill. Finally, magnesium stearate, a lubricant, was added.

Push pull morphine sulphate formulations were coated on a 24 "Hi Coater. A 0.7" x 0.375 "lactose core was used to increase the coater load to 10 kg. The components of the semipermeable membrane were acetyl 95: 5 (wt%: wt%) mixture of cellulose acetate with a content of 39.8% and polyethylene glycol with a molecular weight of 3350. These components are dissolved in a 95: 5 (wt%: wt%) mixture of acetone with 4% solids and water. In addition, an aqueous base coating solution can be used to apply the semipermeable membrane to this system, two 30 mil orifices were perforated in each system, and then the formulation was dried overnight at 37 ° C. to obtain a formulation.

Disclosure of Use of the Invention

The present invention also relates to a method of administering 50 ng to 1,200 mg of morphine to a patient, the method comprising 50 ng to 1,200 mg of morphine, 5 mg to 750 mg of poly (alkylene oxide) having a molecular weight of 100,000 to 650,000, and a molecular weight. From a therapeutic composition comprising from 0.5 mg to 80 ng of poly (vinyl pyrrolidone) of 3,000 to 350,000, consists of orally administering 50 ng to 1,200 mg of morphine selected from the group consisting of morphine and morphine salts to patients over a long period of time.

The method also includes a semipermeable wall that is permeable to aqueous biological fluids and impermeable to drugs; Morphine composition enclosed by semipermeable wall (consisting of 10 to 98% by weight of morphine, 10 to 80% by weight of poly (alkylene oxide) having a molecular weight of 100,000 to 650,000 and 1 to 20% by weight of poly (vinyl pyrrolidone)), and push A composition (formed by compacting from 40 to 99% by weight of poly (alkylene oxide) with a molecular weight of 3,000,000 to 7,750,000, from 0 to 80% by weight of an osmotic agent, and from 0.25 to 25% by weight of hydroxy-alkylcellulose having a molecular weight of 7,500 to 75,000; And outlet means present in the wall for delivering morphine from the formulation (through which the fluid is absorbed into the formulation and the push composition expands and pushes the morphine composition through the outlet means, thereby maintaining the morphine due to the combined action of the formulation. A method of administering 50 ng to 1,200 mg of morphine to a patient from a formulation, which is delivered in a therapeutically effective amount at a controlled rate for a specified time period.

Since the above description is made in the disclosed embodiments, it is understood that changes and modifications may be made in accordance with the principles described without departing from the invention.

Claims (8)

Morphine 50 ng to 1,200 mg; 5 mg to 750 mg of poly (alkylene oxide) having a molecular weight of 100,000 to 650,000; 0.5 mg to 80 mg of poly (vinyl pyrrolidone) having a molecular weight of 3,000 to 350,000; And a therapeutic composition in the form of a tablet contained in a semi-permeable polymer composition case comprising greater than 0 to 7.5 mg of lubricant. The morphine of claim 1, wherein the morphine is morphine hydrobromide, morphine hydrochloride, morphine hydrate, morphine methylbromide, morphine oleate, morphine N-oxide, morphine sulfate, morphine acetate, morphine monobasic phosphate, morphine acetate trihydrate , Morphine salt, morphine ratio (heptafluorobutyrate), morphine ratio (methylcarbamate), morphine ratio (pentafluoropropionate), morphine ratio (pyridine 3-carboxylate), morphine ratio (trifluoro Acetate), morphine bitartrate, morphine chlorhydrate, morphine sulfate pentahydrate, and a morphine base. The therapeutic composition of claim 1, wherein the composition is compressed at a pressure of 1/2 to 25 tons. Morphine compositions comprising 10 to 89 weight percent morphine, 10 to 80 weight percent poly (alkylene oxide) having a molecular weight of 100,000 to 650,000, and 1 to 20 weight percent poly (vinyl pyrrolidone); And an intumescent composition comprising 40 to 99 weight percent poly (alkylene oxide) having a molecular weight of 3,000,000 to 7,500,000, greater than 0 to 59.75 weight percent of an osmotic agent, and 0.25 to 25 weight percent of hydroxyalkylcellulose having a molecular weight of 7,500 to 75,000 and Wherein the morphine composition and the expandable composition are in tablet form surrounded by a semipermeable polymer composition. The formulation of claim 4, wherein the formulation comprises means for releasing the morphine composition from the formulation. The method according to claim 4, wherein the morphine is morphine sulfate pentahydrate, morphine base, morphine chlorhydrate, morphine bitartrate, morphine ratio (trifluoroacetate), morphine ratio (pentafluoropropionate), morphine ratio (Methylcarbonate), morphine ratio (heptafluorobutyrate), morphine salt, morphine acetate trihydrate, morphine monobasic phosphate, morphine acetate, morphine N-oxide, morphine sulfate, morphine oleate, morphine methylbiomy Or a formulation selected from the group consisting of morphine mutate, morphine hydrochloride, and morphine hydrobromide. Morphine 50 ng to 1,200 mg; 5 mg to 750 mg of poly (alkylene oxide) having a molecular weight of 100,000 to 650,000; And 0.5 mg to 80 mg of poly (vinyl pyrrolidone) having a molecular weight of 3,000 to 350,000, and in a semipermeable polymer composition case. Morphine compositions comprising 10 to 89 weight percent morphine, 10 to 80 weight percent poly (alkylene oxide) having a molecular weight of 100,000 to 650,000, and 1 to 20 weight percent poly (vinyl pyrrolidone); And an expandable composition comprising 75 to 99% by weight of poly (alkylene oxide) having a molecular weight of 3,000,000 to 7,500,000, and 1 to 25% by weight of hydroxyalkylcellulose having a molecular weight of 7,500 to 75,000, wherein the morphine composition and the expandable composition are semipermeable. Formulations in the form of tablets surrounded by a polymer composition.